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K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter

Immunity. 2013 Jun 27;38(6):1142-53. doi: 10.1016/j.immuni.2013.05.016.

Abstract

The NLRP3 inflammasome is an important component of the innate immune system. However, its mechanism of activation remains largely unknown. We show that NLRP3 activators including bacterial pore-forming toxins, nigericin, ATP, and particulate matter caused mitochondrial perturbation or the opening of a large membrane pore, but this was not required for NLRP3 activation. Furthermore, reactive oxygen species generation or a change in cell volume was not necessary for NLRP3 activation. Instead, the only common activity induced by all NLRP3 agonists was the permeation of the cell membrane to K⁺ and Na⁺. Notably, reduction of the intracellular K⁺ concentration was sufficient to activate NLRP3, whereas an increase in intracellular Na⁺ modulated but was not strictly required for inflammasome activation. These results provide a unifying model for the activation of the NLRP3 inflammasome in which a drop in cytosolic K⁺ is the common step that is necessary and sufficient for caspase-1 activation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Animals
  • Carrier Proteins / drug effects
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Cell Membrane Permeability / drug effects
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Immunity, Innate
  • Inflammasomes / drug effects
  • Inflammasomes / metabolism*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nigericin / pharmacology
  • Particulate Matter / pharmacology
  • Potassium / metabolism
  • Potassium Channels / drug effects
  • Potassium Channels / metabolism
  • Reactive Oxygen Species / metabolism
  • Sodium Channels / drug effects
  • Sodium Channels / metabolism

Substances

  • Carrier Proteins
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Particulate Matter
  • Potassium Channels
  • Reactive Oxygen Species
  • Sodium Channels
  • Adenosine Triphosphate
  • Caspase 1
  • Nigericin
  • Potassium